1. Technical Field
This document relates to materials and methods for treating cancer (e.g., prostate cancer). For example, this document provides methods for using one or more androgen receptor variant (AR-V) inhibitors (e.g., morpholinos) to treat a mammal having prostate cancer (e.g., castration-resistant prostate cancer).
2. Background Information
Prostate cancer (PCa) is the most frequently diagnosed cancer in males and accounts for an estimated 142,000 deaths in developed countries each year (Torre et al., 2015 CA Cancer J Clin 65:87-108). In normal prostate cells, the androgen receptor (AR) functions as a master transcriptional regulator activated by the androgens, testosterone and dihydrotestosterone; accordingly, PCa presents as an androgen and androgen receptor (AR)-dependent disease (Dehm et al., 2011 Endocr Relat Cancer 18:R183-96). For many, surgery and radiation are curative. However, a significant number of patients are diagnosed with metastatic disease, or experience recurrence after first line interventions. The standard systemic treatment for these men is androgen deprivation therapy (ADT), which includes surgical castration, pharmacologic castration, and antiandrogens to suppress AR transcriptional activity (Dehm et al., 2011 Endocr Relat Cancer 18:R183-96). However, development of resistance and transition to castration-resistant prostate cancer (CRPC) is a major clinical challenge characterized by rising PSA levels (signifying reactivation of AR transcriptional activity), an increase in tumor size, and metastatic spread (Knudsen et al., 2009 Clin Cancer Res 15:4792-8). Second-line ADT drugs that provide a more effective blockade of androgen synthesis (abiraterone), or serve as a higher-affinity AR antagonists (enzalutamide) have recently been approved to treat CRPC (Ryan et al., 2013 N Engl J Med 368:138-48; Beer et al., 2014 N Engl J Med 371:424-33). However, improvements in overall survival still are measured in months and CRPC remains uniformly lethal.